Oral contraceptives first became available in the early 1960's. Since then, a number of regimens for controlling ovulation and contraception by the administration of hormones have become known and are readily available. Oral contraceptive formulations typically contain an estrogen and a progestin. In addition to these steroid active ingredients, the formulation may contain an excipient including various grades of lactose, additives and fillers such as pregelatinized starch and magnesium stearate, and a colorant such as an aluminum oxide lake.
Solvent-based processes, referred to herein as “wet processing” have been commonly employed for many years to make commercial quantities of steroid hormone products, such as oral contraceptives containing steroid active ingredients, According to one well-known process, an active ingredient, such as a steroid hormone, is dissolved in an appropriate volatile solvent and sprayed onto a bed of a pharmaceutically acceptable excipient powder until a desired concentration of the active ingredient per unit weight of powder is achieved. In general, the solvent employed is compatible with the active ingredient and the chosen excipient and can be removed under conditions that will not result in the degradation of the active ingredient. Particularly suitable solvents for use with steroid hormone active ingredients include alcohols such as methanol, ethanol and propanol, ketones such as acetone, hydrocarbons such as ethylene chloride and chloroform, and mixtures of one or more of these solvents with water. The solution is typically sprayed onto the bed of excipient powder in a suitable processor, such as a V-blender with an intensifier bar or a fluid bed processor. The solution and powder are then thoroughly mixed in the processor to ensure uniform dispersion of the active ingredient in the excipient. After mixing, the solvent is removed by the application of heat and/or vacuum to provide a dry mixture.
In an alternative wet processing technique, referred to by those skilled in the art as high sheer wet granulation, the solvent is not sprayed onto the excipient but is, instead, mixed directly with the excipient powder in a high shear blender. Subsequent to mixing, the solvent is removed as described above to provide a dry mixture.
Wet processing provides a number of advantages, including powder blends that have a uniform distribution of active ingredient and that suffer only minimal segregation under usual conditions of storage and handling. Steroid hormone products prepared from these blends typically exhibit excellent content uniformity.
A major disadvantage of these solvent-based processes is that environmentally objectionable organic solvents are generally required in those cases where the steroid active ingredient has poor water solubility. Such solvents often pose safety hazards during handling, in addition to the hazards they present when they are released into the environment. Increasingly, health regulatory authorities are objecting to the use of such solvents due to their toxicity and mutagenicity.
Accordingly, a dry granulation or direct compression process would be preferable for active ingredients that would generally otherwise require the use of an organic solvent. Such dry granulation or direct compression processes will be referred to herein as “dry processing”. Dry processing generally involves fewer steps than solvent-based wet processing and does not require elevated temperatures that can reduce the potency of temperature-sensitive active ingredients. Dry processing is also especially suitable for products that include steroid hormones sensitive to the moisture associated with wet processing via aqueous granulation. The absence of expensive organic solvents and the required evaporation steps also makes dry processing economically more attractive.
U.S. Pat. No. 5,382,434 has proposed pharmaceutical preparations containing steroids (e.g., progestin and/or estrogen) and an excipient (e.g., lactose) made without the use of solvents. According to the '434 patent, at least 80% of the steroid must be bound to the excipient and the excipient must have a low “demixing potential,” which is a measure of content uniformity. The excipient is mixed with the steroid until a uniform mixture is obtained. However, the '434 patent is silent as to release characteristics of these compositions and teaches only a mechanical interaction during the mixing operation.
As those skilled in the art recognize, known steroid hormone products present a number of disadvantages that are not addressed by either wet or dry processing techniques. Steroids exist in various polymorphic forms, defined here to include crystalline, amorphous and solvate forms. In the case of wet processing, the inability to identify the polymorphic form(s) of the potent steroid(s) that exists in a steroid hormone product following removal of the deposited organic solvent is a potential concern both from a physical/chemical stability prospective and from a biopharmaceutical prospective. Unfortunately, known methods of dry processing do not completely eliminate the potential existence of polymorphic forms.
In addition, steroid hormone products prepared by either wet or dry processing methods may present bioavailability problems. Before a drug that is orally administered as a solid can be absorbed, it must first dissolve in the gastrointestinal medium, and then it must be transported in the dissolved state across the gastrointestinal mucosa into the blood stream. As a surrogate test to predict bioavailability prior to commercial release of a drug product, regulatory authorities routinely require that at least 80% of the active ingredient in the product dissolve within 60 minutes in a “physiologically relevant” medium, i.e., a dissolution medium for in-vitro testing. Low dose steroid formulations prepared by known methods of either wet or dry processing have exhibited an undesirable variability in release rate, as measured by dissolution rate techniques in an aqueous medium containing a surfactant. Notably, upon scale up, formulations containing low dose steroids manufactured by dry processing and intended for use as oral contraceptives routinely had slower dissolution rates or at least suffered from a poorly reproducible dissolution profile.
Steroid hormones such as estrogen and progestin are also employed for hormone replacement therapy (HRT). Steroid hormone products used for HRT may contain up to a ten fold higher amount of estrogen and, typically, a lesser amount of progestin than oral contraceptives. Consequently, it is anticipated that such products may experience similar problems related to dissolution. Accordingly, it would also be desirable to reduce or eliminate such problems in the case of HRT steroid hormone products.